1. Field of the Invention
This invention relates to glycemic control compounds. More specifically, the invention relates to glycemic control compounds and methods of treating non-insulin dependent and insulin dependent diabetes with the compounds provided herein.
2. Description of the Related Art
Insulin-Dependent Diabetes Mellitus (IDDM), also known as diabetes mellitus type I, is an autoimmune disease that results in destruction of insulin-producing beta cells of the pancreas. Lack of insulin causes an increase of fasting blood glucose (around 70-120 mg/dL in non-diabetic people) that begins to appear in the urine above the renal threshold (about 190-200 mg/dL in most people), thereby resulting in the symptom with which the disease was identified in antiquity, sweet urine. Glycosuria, or glucose in the urine, causes patients to urinate more frequently and drink more than normal (polydipsia). These were the classic characteristic symptoms which prompted discovery of the disease.
Type I diabetes is lethal unless treated with exogenous insulin. Injection is the traditional, and still most common, method for administering insulin. Jet injection, indwelling catheters, and inhaled insulin have also been available at various times and there are several experimental methods as well.
Insulin resistance is a classic feature of many human disease conditions, such as in another type of diabetes, Non-Insulin-Dependent Diabetes Mellitus (NIDDM); obesity; hypertension; aging; etc. Diabetes mellitus is a disorder of carbohydrate metabolism, characterized by hyperglycemia and glycosuria resulting from inadequate production or utilization of insulin. NIDDM is a form of diabetes where utilization of insulin is inadequate. It occurs predominantly in adults, where adequate production of insulin is available for use, yet a defect exists in insulin-mediated utilization and metabolism of glucose and peripheral tissues. For some people with diabetes, a mutation in the gene(s) coding for insulin, for insulin receptor and/or for insulin-mediated signal transduction factor(s) leads to ineffective insulin and/or insulin-mediated effects, impairing the utilization or metabolism of glucose.
Diabetes mellitus is a disease affecting approximately 7.5 million people in the United States. The underlying cause of this disease is diminished or absent insulin production by the islets of Langerhans in the pancreas. Of the 7.5 million diagnosed diabetics in the United States, approximately one-third are treated using insulin replacement therapy. Those patients receiving insulin typically self-administer one or more doses of the drug per day by subcutaneous injection. Insulin is a polypeptide with a nominal molecular weight of 6,000 Daltons. Insulin has traditionally been produced by processing pig and cow pancreas to allow isolation of the natural product. More recently, recombinant technology has made it possible to produce human insulin in vitro. It is currently the common practice in the United States to institute the use of recombinant human insulin in all patients beginning insulin therapy.
Diabetes mellitus often develops from certain at risk populations; it is known that one such population are individuals with impaired glucose tolerance (IGT). The usual meaning of impaired glucose tolerance is that it is a condition intermediate between non-insulin-dependent diabetes mellitus and normal glucose tolerance. IGT is diagnosed by a procedure wherein an affected person's postprandial glucose response is determined to be abnormal as assessed by postprandial plasma glucose levels. In this test, a measured amount of glucose is given to the patient and blood glucose level measured at regular intervals, usually every ½ hour for the first two hours and every hour thereafter. In a “normal,” or non-IGT individual, glucose levels rise during the first two hours to a level less than 140 mg/dl and then drop rapidly. In an impaired individual (IGT), the blood glucose levels are higher and the drop-off level is at a slower rate. A high percentage of the impaired (IGT) population is known to progress to non-insulin dependent diabetes mellitus.
The pathophysiology of non-insulin-dependent diabetes mellitus (NIDDM) consists of three major components: (1) peripheral insulin resistance, (2) increased hepatic glucose production, and (3) impaired insulin secretion. Intense research has been devoted to each of these areas, independently, in order to determine which abnormality is primary and which are secondary. The prevailing view is that a rational therapeutic pharmacological approach should involve intervention in insulin resistance to improve glucose homeostasis. As a result of the focus on individual abnormalities, several model therapies were developed to regulate glucose homeostasis in Type II diabetic patients.
The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications of an elevated blood glucose.
One such therapy utilizes sulfonyl ureas to target one mechanism of hyperglycemia by augmenting insulin secretion from the beta cells. Since 1995, three new classes of agents have been added to the anti-diabetes armamentarium for the management of hyperglycemia. Metformin, a biguanide, targets additional mechanisms of hyperglycemia by inhibiting hepatic glucose production and enhancing peripheral glucose uptake and thereby reduce insulin resistance; thiazolidinediones, such as troglitazone, rosiglitazone and pioglitazone, decrease peripheral insulin resistance; and alpha-glucosidase inhibitors, such as acarbose and mioglitol, help control postprandial glucose excursion by delaying absorption of dietary carbohydrate. These agents are all indicated as monotherapy, and some are indicated for use in combination therapy, generally, after monotherapy has been found to be inadequate; yet, many side effects exist in the currently available oral agents.
To this end, there is a need for an orally administered agent for IDDM and NIDDM that can be substituted for the currently available therapies with better results and less side effects and toxicity.